Adipose tissue distribution is an important determinant of obesity-related comorbidities. Peripheral obesity (subcutaneous/gluteofemoral adipose tissue accumulation) is associated with improved insulin sensitivity and lower risk for metabolic co-morbidities such as dyslipidemia, cardiovascular disease, insulin resistance and type-2-diabetes. It has been postulated that the protective effects of peripheral adipose tissue occur via its ability to sequester surplus lipid and thus serve as a metabolic sink. We propose to systematically examine how peripheral adipose tissue serves a protective role in obesity using a model in which various amounts of peripheral adipose tissue are removed. In support of this, removal of peripheral adipose tissue leads to impaired glucose tolerance and tissue-specific lipid accumulation in mice. Aim 1 investigates the role of peripheral adipose tissue in glucose homeostasis. Aim 2 will examine how peripheral adipose tissue removal leads to impaired glucose tolerance. Overall, completion of these aims will provide new insight into how peripheral adipose tissue regulates glucose homeostasis. Results from these studies will fundamentally advance the field of adipose tissue biology and increase our understanding of potential therapeutic strategies for obesity prevention and treatment.